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. 2023 Jun 26;15:243–259. doi: 10.2147/RRU.S385257

Figure 2.

Figure 2

PARP inhibitors mechanism of action. DNA damage and PARPsThe most common type of DNA damage is DNA Single-Strand Break or SSB (1), which is repaired mostly by PARP-dependent Base Excision Repair (BER) pathway (2).The PARP (Poly ADP-Ribose Polymerase) enzyme family can catalyze the transfer of ADP-ribose to target proteins. Some isoforms of PARP family have the function of detecting and initiating an immediate response to DNA SSBs. Once a SSB is detected, one of these PARPs binds to the DNA (3) and undergoes a conformational change, allowing β-NAD+ (the PARP co-factor) to bind to the active site of the enzyme (4). At this point, the enzyme uses the hydrolysis of β-NAD+ to catalyze the transfer of ADP-Ribose moieties onto target proteins, leading to the synthesis (PARylation) of a Polymeric ADP-Ribose (PAR) chain (5). This step allows the recruitment (via their PAR-binding domains) of DNA repair effectors(6), which are required for efficient DNA repair (7). The process ends with the degradation of PAR chains via Poly (ADP-ribose) Glycohydrolase (PARG) and the release of PARP and repair enzymes. PARP inhibitorsPARP inhibitors or PARPi (8) induce catalytic inhibition of PARP-dependent repair (preventing PARylation) and binding of PARP on damaged DNA (9). Failure to repair SSBs leads to DSBs (Double-Strand Breaks) during DNA replication, thus PARP inhibition induces further DNA damage (10). Nevertheless, DNA damage can also be repaired through Homologous Recombination (HR) mechanisms, so HR-proficient cells can repair DSBs originated from SSBs and survive (11), while HRdeficient cells that cannot repair DSBs die (12). Usually, cancer cells are mutated in one of their DNA repair pathways. For example, BRCA1 and BRCA2 encode key components of the HRR mechanism, so mutations of these two genes lead to the inability to repair DSBs. Accordingly, PARP inhibitors exploit a principle called synthetic lethality, in which two conditions that independently of each other allow the cell to survive together cause cell death.